Piperazine derivatives as 5-HT1B antagonists

ABSTRACT

Piperazine derivatives of formula(1),                    
     processes for their preparation, pharmaceutical compositions containing them in the treatment of CNS and other disorders and in their use in therapy as 5-HT 1B  antagonists are disclosed herein.

This application is a Section 365(c) application based on PCTapplication serial number PCT/EP00/09442 filed Sep. 21, 2000 designatingthe US and claiming priority from GB 0013873.5, filed Jun. 7, 2000; GB0001936.4, filed Jan. 27, 2000; and GB 9922831.4, filed Sep. 25, 1999.

The present invention relates to novel piperazine derivatives, processesfor their preparation, pharmaceutical compositions containing the sameand to their use in the treatment of CNS and other disorders.

WO 95/06637 discloses a series of piperazine derivatives which are saidto possess 5-HT_(1D) receptor antagonist activity. These compounds arealleged to be of use in the treatment of various CNS disorders such asdepression. The human 5-HT_(1D) receptor is now known to be encoded bytwo distinct genes initially designated 5-HT_(1Dα)and 5-HT_(1Dβ)andsubsequently redesignated as 5-HT_(1D) and 5-HT_(1B) respectively (P. R.Hartig et al, Trends in Pharmacological Science, 1996, 17, 103-105). WO98/50538 and WO 98/47885 disclose a series of piperazine derivativesthat are said to exhibit combined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D)receptor antagonist activity. WO 98/27058 discloses a series ofcarboxamide derivatives that are claimed to be 5-HT₆ receptorantagonists.

A structurally novel class of compounds has now been found which alsoexhibit 5-HT_(1B) receptor activity. In a first aspect, the presentinvention therefore provides a compound of formula (I) or apharmaceutically acceptable salt thereof:

in which R^(a) is a group of formula (i)

wherein P¹ is phenyl, naphthyl or heteroaryl;

R¹ is halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, COC₁₋₆alkyl, C₁₋₆alkoxy,hydroxy, hydroxyC₁₋₆alkyl, nitro, CF₃, cyano, SR⁶, SOR⁶, SO₂R⁶, SO₂R⁶,SO₂NR⁶R⁷, CO₂R⁶, CONR⁶R⁷, OCONR⁶R⁷, NR⁶R⁷, NR⁶CO₂R⁷, NR⁶CONR⁷R⁸,CR⁶═NOR⁷ where R⁶, R⁷ and R⁸ are independently hydrogen or C₁₋₆alkyl;

a is 0, 1, 2 or 3;

or R^(a) is a group of formula (ii)

 wherein

P² is phenyl, naphthyl, heteroaryl or a 5 to 7 membered heterocyclicring;

P³ is phenyl, naphthyl or heteroaryl;

A is a bond or oxygen, carbonyl, CH₂ or NR⁴ where R⁴ is hydrogen orC₁₋₆alkyl;

R² is as defined above for R¹ in formula (i) or R² is heteroaryloptionally substituted by C₁₋₆alkyl, halogen or COC₁₋₆alkyl or is a 5-7membered heterocyclic ring optionally substituted by oxo;

R³ is halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, COC₁₋₆alkyl,hydroxy, nitro, CF₃, cyano, CO₂R⁶, CONR⁶R⁷, NR⁶R⁷ where R⁶ and R⁷ are asdefined above;

b and c are independently 0, 1, 2 or 3;

Y is a single bond, CH₂, O or NR⁵ where R⁵ is hydrogen or C₁₋₆alkyl;

W is —(CR⁹R¹⁰)_(t)— where t is 2, 3 or 4 and R⁹ and R¹⁰ areindependently hydrogen or C₁₋₆alkyl or W is a group CH═CH;

R^(b) is hydrogen, halogen, hydroxy, C₁₋₆alkyl, CF₃, COC₁₋₆alkyl, cyanoor C₁₋₆alkoxy;

R^(c) is hydrogen or C₁₋₆alkyl;

R^(d) and R^(e) are independently C₁₋₄alkyl.

Alkyl groups, whether alone or as part of another group, may be straightchain or branched. The term ‘halogen’ is used herein to describe, unlessotherwise stated, a group selected from fluorine, chlorine, bromine oriodine.

Where used herein the term naphthyl is intended, unless otherwisestated, to denote both naphth-1-yl and naphth-2-yl groups.

The term “heteroaryl” is intended to mean an aromatic or a benzofusedaromatic ring containing 1 to 3 heteroatoms selected from oxygen,nitrogen and sulphur. Suitable examples of such aromatic rings includethienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl,oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl,pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of suchbenzofused aromatic rings include quinolinyl, isoquinolinyl, indolyl,benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl and the like.

The term “5-7 membered heterocyclic ring” is used herein to mean a nonaromatic ring containing 1 to 3 heteroatoms selected from oxygen,nitrogen and sulphur. Suitable examples of such non aromatic ringsinclude piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl.

The heteroaryl and 5-7 membered heterocyclic rings, as described above,may be linked to the remainder of the molecule via a carbon atom or,when present, a suitable nitrogen atom.

Within the Definition of R^(a) Formula (i)

When P¹ is heteroaryl a preferred example is pyridyl. Preferably P¹ isphenyl or naphthyl, most preferably phenyl.

When a is other than 0, preferred R¹ groups include halogen(particularly fluoro or chloro), C₁₋₆alkyl group (particularly methyl),CF₃ and cyano. When a is 2 or 3 the groups R¹ can be the same ordifferent.

Preferably a is 1 or 2, most preferably 2.

Within the Definition of R^(a) Formula (ii)

Preferably A is a bond.

When P³ is heteroaryl preferred examples include quinolinyl andpyrazolyl. P³ is preferably phenyl or naphthyl. A preferred substitutionarrangement for such naphthyl groups is 1,4 or 1,5, that is to say, anaphth-1-yl group in which the group A is attached at the 4 or 5position respectively.

P² is preferably phenyl, a heteroaryl group such as pyridyl, pyrazinyl,oxadiazolyl or oxazolyl or P² is a 5-7 membered heterocycle such aspiperidinyl.

When b is other than 0, preferred R² groups include halogen(particularly chloro), C₁₋₆alkyl group (particularly methyl), heteroaryl(particularly oxadiazolyl optionally substituted by C₁₋₆alkyl) or a 5-7membered heterocyclic ring (particularly 2-oxo pyrrolidinyl). When b is2 or 3 the groups R² may be the same or different. Preferably b is 0, 1or 2.

When c is other than 0, preferred R³ groups are halogen (particularlychloro) and C₁₋₆alkyl group (particularly methyl). When c is 2 or 3 thegroups R³ may be the same or different. Preferably c is 0 or 1.

A preferred group of formula (ii) is that in which A is a single bond,P² is pyridyl (particularly 2-pyridyl) and P³ is naphthyl particularlynaphth-1-yl). A further preferred group of formula (ii) is that in whichA is a single bond, P² is pyridyl and P³ is phenyl. Such groups may beoptionally substituted by the preferred R² and R³ groups as describedabove.

Y is preferably a single bond, CH₂ or a NH group.

It will be appreciated that when W is a group —CH═CH— an indole ring isformed. Within the definition of the group W, the groups R⁹ and R¹⁰ areeach preferably hydrogen and t is preferably 2 or 3, most preferably 2.

R^(b) is preferably hydrogen, C₁₋₆alkoxy group (particularly methoxy) orC₁₋₆alkyl group (particularly methyl).

R^(c) is preferably hydrogen or methyl.

Preferably both R^(d) and R^(e) are methyl.

Preferred compounds of this invention are examples E1-E73 (as describedbelow) or a pharmaceutically acceptable salt thereof. Particularlypreferred compounds according to this invention are:

cis-1-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin-1-yl)indole,

cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline,

cis-1-[(2,3dichlorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindoline

cis-6-(3,5-dimethylpiperazin-1-yl)-5-methoxy-1-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]indoline,

cis-1-[(3-chloro-2-fluorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindole,

cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-fluoro-6-(3,4,5-trimethylpiperazin-1-yl)indole,

cis-1-[2-chloro-3-(trifluoromethyl)phenyl)aminocarbonyl]-5-methyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline

or a pharmaceutically acceptable salts thereof.

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be hydrated orsolvated. This invention includes within its scope stoichiometrichydrates as well as compounds containing variable amounts of water.

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. diastereomers and enantiomers) and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated one from the other by the usual methods, or any given isomermay be obtained by stereospecific or asymmetric synthesis. The inventionalso extends to any tautomeric forms and mixtures thereof.

Compounds of the invention can be prepared using procedures known in theart. In a further aspect the present invention also provides a processfor the preparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof which comprises either:

(a) where Y is NH, coupling a compound of formula (II):

R^(a)—N—(C═O)  (II)

in which R^(a) is as defined in formula (I) with a compound of formula(III):

in which W, R^(b), R^(c), R^(d) and R^(e) are as defined in formula (I);or

(b) where Y is NR⁵, reacting a compound of formula (IV)

R^(a)—NR⁵H  (IV)

in which R^(a) and R⁵ are as defined in formula (I) with a compound offormula (III) as defined above together with an appropriate urea formingagent; or

(c) where Y is a single bond, CH₂ or O, reacting a compound of formula(V)

R^(a)—Y—(C═O)—L  (V)

in which R^(a) is as defined in formula (I) and L is an appropriateleaving group, with a compound of formula (III) as defined above; andoptionally thereafter for either process (a), (b) or (c):

removing any protecting groups,

converting a compound of formula (I) into another compound of formula(I),

forming a pharmaceutically acceptable salt.

The reaction in process (a) is conveniently effected in an organicsolvent such as dichloromethane.

In process (b) the urea forming agent can be carbonyl diimidazole,triphosgene or phosgene, and carried out in an inert organic solventsuch as dimethylformamide, tetrahydrofuran or dichloromethane at ambientor elevated temperature in the presence of a base such as triethylamineor pyridine.

In process (c) the leaving group L may be a halogen e.g. chloro groupand the reaction may be carried out in an inert organic solvent such astetrahydrofuran or dichloromethane at ambient or elevated temperature inthe presence of a base such as triethylamine or pyridine. AlternativelyL may be an O-benzotriazole group, prepared from hydroxybenzotriazoleand a carbodiimide, and the reaction may be carried out in an inertorganic solvent such as tetrahydrofuran, dichloromethane ordimethylformamide at ambient or elevated temperature.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard techniques. The following examples are givenby way of illustration of this point rather than limitation. Forcompounds of formula (I) wherein R^(c) is hydrogen, it is possible tointroduce a C₁₋₆alkyl group by conventional alkylation using 1 molarequivalent of a C₁₋₆alkyl halide and 1 molar equivalent of a suitablebase in an inert solvent. For compounds of formula (I) wherein W is agroup —CH₂CH₂—, it is possible to convert this to a group wherein W is—CH═CH— with an oxidising agent such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an inert solvent such asdichloromethane or toluene.

Intermediate compounds of formula (II), (III), (IV) and (V) are eithercommercially available or can be prepared using methods describedherein, by methods known to those skilled in the art or by analogousmethods thereto. For example, where intermediates of formula (V) arederived from phenylacetic acids, the latter may be prepared from thecorresponding benzoic acids by standard homologation methods involvingreduction to the benzyl alcohol, followed by conversion to the benzylbromide, displacement with an inorganic cyanide to afford thebenzonitrile, followed by acid or base hydrolysis.

It will be appreciated to those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques can beused. For example, primary amines can be protected as phthalimide,benzyl, benzyloxycarbonyl or trityl derivatives. Carboxylic acid groupscan be protected as esters. Aldehyde or ketone groups can be protectedas acetals, ketals, thioacetals or thioketals. Deprotection of suchgroups is achieved using conventional procedures well known in the art.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

The involvement of serotonin (5-hydroxytryptamine; 5-HT) receptors in anumber of pharmacological effects has been reviewed by R. A. Glennon in“Serotonin Receptors: Clinical Implications”, Neuroscience andBehavioural Reviews, 1990, 14, 35 and by L. O. Wilkinson and C. T.Dourish in “Serotonin Receptor Subtypes: Basic and Clinical Aspects” S.Peroutka Ed., John Wiley and Sons, New York, 1991 p. 147.

Serotonin receptors have been implicated in pharmacological effects suchas mood disorders including depression, seasonal affective disorder anddysthymia, anxiety disorders, including generalized anxiety, panicdisorder, agoraphobia, social phobia, obsessive compulsive disorder andpost-traumatic stress disorder, memory disorders, including dementia,amnesic disorders and age-associated memory impairment; disorders ofeating behaviours, including anorexia nervosa and bulimia nervosa, sleepdisorders (including disturbances of circadian rhythm), motor disorderssuch as Parkinson's disease, dementia in Parkinson's disease,neuroleptic-induced Parkinsonism and tardive dyskinesias, pain disordersas well as other psychiatric disorders such as schizophrenia andpsychosis. Serotonin receptor ligands have been shown to be of use inthe treatment of emesis and nausea and may also be of use in endocrinedisorders such as hyperlactinaemia, vasospasm (particularly in thecerebral vasculature), cerebellar ataxia and hypertension, as well asdisorders of the gastrointestinal tract where changes in motility andsecretion are involved. They may also be of use in the treatment ofpre-menstrual tension, sexual dysfunction and hypothermia.

Ligands with high affinity for the 5-HT₁ receptors are well recognisedas having therapeutic utility for the treatment of the above conditions.It has been suggested that a selective 5-HT_(1B) receptor antagonistshould act as a fast onset antidepressant (P. Blier Trends Pharmacol.Sci. 1994, 15, 220).

The present invention also provides for a compound of formula (I) or apharmaceutically acceptable salt for use in the treatment of theaforementioned disorders. In particular, the invention provides for acompound of formula (I) or a pharmaceutically acceptable salt for use inthe treatment or prophylaxis of depression.

In a further aspect the invention provides a method of treatingdisorders where an antagonist of the 5-HT_(1B) receptor is beneficial,particularly the aforementioned disorders, which comprises administeringa safe and therapeutically effective amount of compound of formula (I)or a pharmaceutically acceptable salt to a patient in need thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment or prophylaxis ofdisorders in which an antagonist of the 5-HT_(1B) receptor isbeneficial, particularly the aforementioned disorders, more particularlydepression.

The affinities of the compounds of this invention for the 5-HT_(1B)receptor can be determined by the following radioligand binding assay.CHO cells expressing 5-HT_(1B) receptors (4×10⁷ cells/ml) arehomogenised in Tris buffer Mg²⁺ and stored in 1.0 ml aliquots. 0.4 ml ofa cell suspension is incubated with [³H]-5-HT (4 nM) in Tris Mg HClbuffer (pH 7.7) and test drug, at 37° C. for 45 minutes. Each test drugis tested at 10 concentrations (0.01 mM to 0.3 nM final concentration),with non-specific binding defined using 0.01 mM 5-HT. The total assayvolume is 0.5 ml. Incubation is stopped by rapid filtration using aTomtec Harvester (filters pre-washed in 0.3% polyethylenimine) andradioactivity measured by Topcount scintillation counting. pKi valuesare calculated from the IC₅₀ generated by an iterative least squarescurve fitting programme.

All examples tested in accordance with this radioligand binding assaywere found to have a pKi>7.3 at 5-HT_(1B) receptors with manydemonstrating a pKi in the higher range of 8.0-9.2.

The selectivity of the compounds of this invention for 5-HT_(1B)receptors can be determined using binding assay methods which are wellknown to those skilled in the art. All examples tested were found tohave a greater than a 10-fold selectivity over 5-HT_(1D) receptors and agreater than 50-fold selectivity over other binding sites within theCNS, in particular, other 5-HT receptor sub-types and dopaminergicreceptors. Many examples were found to have a greater than a 30foldselectivity over 5-HT_(1D) receptors and a greater than 80-foldselectivity over other binding sites.

The intrinsic activity of the compounds of this invention can bedetermined according to the following procedure. CHO cell membranesstably expressing human 5-HT_(1B) receptors are homogenised inHEPES/EDTA buffer and stored in 1 ml aliquots, and [³⁵S]GTPγS bindingstudies are carried out essentially as described by Lazareno et al.,(Life Sci., 1993, 52, 449) with some minor modifications. Membranes from10⁶ cells are pre-incubated at 30° C. for 30 minutes in 20 mM HEPESbuffer (pH 7.4) in the presence of MgCl₂ (3 mM), NaCl (100 mM), GDP (10μM) and ascorbate (0.2 mM), with or without compounds. The reaction isstarted by the addition of 50 μl of [³⁵S]GTPγS (100 pm, assayconcentration) followed by a further 30 minutes incubation at 30° C.Non-specific binding was determined using non-radiolabelled GTPγS (20μM) added prior to the membranes. The reaction is terminated by rapidfiltration through Whatman GF/B grade filters followed by 5×1 ml washeswith ice cold HEPES (20 mM)/MgCl₂ (3 mM) buffer. Radioactivity ismeasured using liquid scintillation spectrometry. This procedure ishereafter referred to as the [³⁵S]GTPγS functional assay.

It has been found, using the [³⁵S]GTPγS functional assay, that certaincompounds of formula (I) show varying levels of intrinsic efficacy,which is defined by a scale in which the value 1.0 defines the maximumresponse elicited by the agonist 5-HT, 0.0 defines antagonism and anegative value indicates inverse agonism. The difficulties in describingintrinsic activity of drugs acting at G protein coupled receptors isrecognised in the art (Hoyer and Boddeke, Trends in PharmacologicalSciences, July 1993, [Vol. 14], page 270-275). We believe that howeverthese ligands are classified according to this functional assay, thecompounds of this invention will be useful antidepressants in vivo. Itis believed that the preferred compounds of this invention will display5-HT_(1B) antagonist activity in vivo and that such compounds will havea rapid onset of action. A rapid onset of action is particularlyadvantageous for antidepressant compounds: by ‘rapid onset of action’ wemean that a therapeutic response is seen within 7 days from firstadministration of the compound, as opposed to a period of about 21 daysor more which is typical of SSRI's, tricyclic antidepressants andbuspirone.

Compounds of formula (I) which have an intrinsic activity of 0.5 or lessin the in vitro [³⁵S]GTPγS functional assay are preferred, as thesecompounds are more likely to be full antagonists in vivo. Particularlypreferred compounds of this invention have an intrinsic activity in therange 0.0-0.3 or are inverse agonists in this functional assay.

It has been found that the compounds of this invention have aparticularly advantageous profile in that they demonstrate high affinityand selectivity for the 5-HT_(1B) receptor together with low intrinsicactivity in the [³⁵S]GTPγS functional assay.

It will be appreciated by those skilled in the art that the compoundsaccording to the invention may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, differentantidepressant agents.

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice. The present invention alsoprovides a pharmaceutical composition, which comprises a compound offormula (I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three times a day. Such therapymay extend for a number of weeks or months.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following descriptions and Examples illustrate the preparation ofcompounds of the invention.

Description 1 1-Acetyl-6-bromo-5-methoxyindoline (D1)

A stirred solution of 1-acetyl-6-bromoindolin-5-ol (Tetrahedron 1973,29(8), 1115; 40 g, 0.15 mole) in DMF (500 ml) was treated with K₂CO₃ (61g, 0.45 mole) and iodomethane (11.7 ml, 0.19 mole) and maintained atroom temperature for 20 h, then concentrated under vacuum to 200 ml. Theresidue was treated with water (200 ml) and the precipitate filteredoff, dried and recrystallised from EtOAc to afford the title compound asa white solid (35.7 g, 85%).

Description 2cis-1-Acetyl-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline (D2)

A mixture of palladium (II) acetate (500 mg),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.0 g) and cesium carbonate(10.3 g) in dry degassed 1,4-dioxane (120 ml) under argon was sonicatedat 28° C. for 0.5 h producing a pink heterogeneous mixture. This wastreated with D1 (6.0 g, 22 mmole) followed bycis-1,2,6-trimethylpiperazine (J. Med. Chem. 1968, 11, 592; 4.8 g, 38mmole) and heated with rapid stirring at reflux for 70 h. The mixturewas allowed to cool, filtered, then concentrated under vacuum. Theresidue was treated with water and extracted with EtOAc. The organicsolution was then extracted with 1M HCl acid and the aqueous extract wasbasified by addition of K₂CO₃ and extracted with EtOAc. The extract wasdried (Na₂SO₄) and concentrated under vacuum to leave an orange solid,which was chromatographed on silica gel eluting with 0-10% MeOH/DCM toafford the required product as a pale yellow solid (1.6 g, 23%).

Description 3 cis-5-Methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D3)

A stirred solution of D2 (1.6 g, 5 mmole) in 2M HCl acid (50 ml) washeated under reflux for 2 h, then the solution was allowed to cool,basified with K₂CO₃ and extracted with DCM. The extract was dried(Na₂SO₄) and concentrated under vacuum to afford the title compound as apale orange solid (1.4 g, 100%).

Description 4cis-1-Acetyl-6-(4-benzyl-3,5-dimethylpiperazin-1-yl)-5-methoxyindoline(D4)

The title compound was prepared in 43% yield fromcis-1-benzyl-2,6-dimethylpiperazine (Org. Prep. Proc. 1976, 8, 19) andD1 using a similar procedure to Description 2.

Description 5cis-6-(4-Benzyl-3,5-dimethylpiperazin-1-yl)-5-methoxyindoline (D5)

The title compound was prepared from D4 by a similar procedure toDescription 3 as a beige solid (100%)

Description 6cis-6-(4-Benzyl-3,5-dimethylpiperazin-1-yl)-5-methoxy-1-[4-(6-methylpyridin-2-yl)-1-naphthoyl]indoline(D6)

The title compound was prepared from D5 and D13 following a similarprocedure to Example 1 as a white solid (85%).

Description 7 Methyl 4-(trimethylstannyl)-1-naphthoate (D7)

A stirred solution of methyl 4bromo-1-naphthoate (Collect. Czech. Chem.Commun. 1997, 62(11), 1737; 7.3 g, 28 mmole) in degassed toluene (300ml) was treated with hexamethylditin (10 g, 31 mmole) andtetrakis(triphenylphosphine)palladium(0) (720 mg) and heated at refluxunder argon for 3 h. On cooling, the mixture was filtered through Celite(Diatomaceous Earth), concentrated under vacuum and the residuechromatographed on silica gel eluting with 0-3% ether/60-80 petrol toafford the title compound as a colourless oil (9.06 g, 94%).

Description 8 Methyl 4-(pyridin-4-yl)-1-naphthoate (D8)

A stirred solution of D7 (9.06 g, 26 mmole) in dry degassed DMF (150 ml)was treated with copper (I) iodide (495 mg, 2.6 mmole),dichlorobis(triphenylphosphine)palladium(II) (1.52 g, 2.2 mmole) and4-bromopyridine (prepared by suspending the HCl salt (6.07 g, 31 mmole)in 40% KOH solution, extracting with toluene and adding the driedtoluene solution to the reaction). The mixture was heated at refluxunder argon for 5 h and allowed to cool before removing the DMF undervacuum. The residue was partitioned between EtOAc and 10% NaHCO₃solution and the organics dried (Na₂SO₄) and chromatographed on silicagel eluting with EtOAc to afford the title compound as a white solid(4.1 g, 60%).

Description 9 Methyl 4-(1-methylpiperidin-4-yl)-1-naphthoate (D9)

A stirred solution of D8 (2.0 g, 7.6 mmole) in acetone (20 ml) wastreated with methyl iodide (1.0 ml, 15 mmole), stirred for 0.5 h andthen allowed to stand at room temperature for 2 days. The resultantyellow precipitate was filtered off to afford the pyridinium salt asyellow crystals (2.87 g). This was dissolved in EtOH (30 ml) and DMF (90ml) and was hydrogenated at 50 psi (344.8 KPa) and room temp over PtO₂for 24 h. The mixture was filtered through Celite (Diatomaceous Earth)and the filtrate concentrated under vacuum to a brown oil. This waspartitioned between DCM and 10% NaHCO₃ solution and the organic solutionseparated, dried (Na₂SO₄) and concentrated under vacuum to afford thetitle compound as a brown oil (1.82 g, 91%).

Description 10 Methyl 4-(piperidin-4-yl)-1-naphthoate (D10)

A solution of D9 (0.39 g, 1.4 mmole) in DCM (30 ml) was treated withiPr₂EtN (0.26 g, 2 mmole) followed by 1-chloroethyl chloroformate (0.29g, 2 mmole) and stirred at room temperature for 3 h, then concentratedunder vacuum and the residue treated with MeOH (30 ml) and heated underreflux for 1 h. The mixture was allowed to cool and the solid filteredoff, washed with Et₂O and dried. This was treated with 10% Na₂CO₃solution, extracted with DCM and the extract dried and concentratedunder vacuum to afford the title compound as a colourless oil (0.33 g,88%).

Description 11 4-(1-tert-Butoxycarbonylpiperidin-4-yl)-1-naphthoic acid(D11)

A solution of D10 (0.33 g, 1.2 mmole) in DCM (30 ml) was treated withdi-tert-butyl dicarbonate (0.28 g, 1.25 mmole) and stirred at roomtemperature for 20 h, then concentrated under vacuum to leave a whitesolid (0.44 g). This was dissolved in THF (15 ml) and MeOH (15 ml),treated with LiOH (85 mg) in water (10 ml) and stirred at roomtemperature for 20 h, then concentrated under vacuum to approx. 10 ml.The residue was treated with excess 10% aqueous citric acid andextracted with EtOAc. The extract was dried and concentrated undervacuum to afford the title compound as a white solid (0.41 g, 97%).

Description 12cis-1-[4-(1-tert-Butoxycarbonylpiperidin-4-yl)-1-naphthoyl]-5methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D12)

The title compound was prepared from D11 and D3 using a similarprocedure to Example 8 as a pink solid (52%).

Description 13 4-(6-Methylpyridin-2-yl)-1-naphthoic acid (D13)

The title compound was prepared from D7 and 2-bromo-6-methylpyridineusing a similar method to Description 8 (45%), followed by hydrolysis ofthe methyl ester using 1M NaOH solution (69%) to afford a white solid.

Description 14 Methyl 4-(trimethylstannyl)1-naphthylacetate (D14)

The title compound was prepared from methyl 4-bromo-1-naphthylacetate(Zh. Org. Khim. 1966, 2, 1852) using a similar procedure to Description7 as a colourless oil (69%).

Description 15 4-(6-Methylpyridin-2-yl)-1-naphthylacetic acid (D15)

The title compound was prepared from D14 and 2-bromo-6-methylpyridineusing a similar method to Description 8 (32%), followed by hydrolysis ofthe methyl ester using 1M NaOH solution (80%) to afford a white solid.

Description 16 4-Formyl-1-naphthylboronic acid (D16)

A mixture of K10 montmorillonite clay (75 g) and trimethylorthoformate(75 ml) in methanol (75 ml) was stirred at room temperature for 0.5 h,then filtered. The solid was added to a stirred solution of4-bromo-1-naphthylcarboxaldehyde (JP 01113354 [1989], 25.70 g, 0.11mole) in DCM (300 ml). After 18 h the mixture was filtered, washed with20% K₂CO₃ solution (100 ml), dried and concentrated in vacuo to affordthe dimethyl acetal as a yellow oil (29.05 g 95%), which was dissolvedin anhydrous THF (300 ml) at −70° C. and treated with a 1.6M solution ofn-butyllithium in THF (78 ml, 0.12 mole). After 1 h triisopropyl borate(24.4 g, 0.13 mole) was added over 0.25 h, the mixture stirred for 1 hat −70° C. then poured into 2M HCl (500 ml). The mixture wasconcentrated to 50% volume in vacuo, and extra ted with EtOAc. Theorganic solution was then extracted with 10% NaOH solution (4×50 ml) andthe combined aqueous solution acidified with 6M HCl and extracted withDCM (3×100 ml). The extract was dried and concentrated to dryness invacuo to afford the title compound as a yellow-green powder (13.15 g,64%).

Description 17 4-Carboxy-1-naphthylboronic acid (D17)

To a stirred solution of D16 (0.25 g, 1.25 mmole) and NaOH (0.15 g, 3.75mmole) in water (5 ml) at 0° C. was added dropwise a solution of KMnO₄(0.19 g. 0.120 mmole) in water (5 ml). After 0.25 h sodiummetabisulphite (excess) was added and the mixture acidified with 6M HCland extracted with EtOAc (3×15 ml). The extracts were dried andconcentrated to dryness to afford the title compound as cream powder(0.21 g, 78%).

Description 18 4-(2,6-Dimethylpyridin-3-yl)-1-naphthoic acid (D18)

A stirred mixture of D17 (0.32 g, 1.5 mmole),3-bromo-2,6-dimethylpyridine hydrochloride (Synthesis 1974, 4, 293; 0.37g, 1.6 mmole), Na₂CO₃ (0.48 g, 5.6 mmole) andtetrakis(triphenylphosphine)palladium (0) (0.08 g, 0.07 mmole) in 50%DME/water (20 ml) was heated at reflux under argon for 18 h. The mixturewas concentrated in vacuo to 50% volume, diluted with water (20 ml),washed with EtOAc (2×10 ml), acidified with 2M HCl to pH 4 and extractedwith DCM (3×25 ml). The combined extract was dried and evaporated todryness. The residue was triturated in Et₂O to afford the title compoundas a buff powder (0.29 g, 69%).

Description 19 4-(3,6-Dimethylpyrazin-2-yl)-1-naphthoic acid (D19)

The title compound was prepared from D17 and2-chloro-3,6-dimethylpyrazine using a similar procedure to Description18 as a cream powder (50%).

Description 20 4-(1-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-naphthoicacid (D20)

The title compound was prepared from3-bromo-1-methyl-6-oxo-1,6-dihydropyridine (Khim.Geterotsikl. soedin.1982, 12, 1662) and D17 using a similar procedure to Description 18 as abuff powder (78%).

Description 21cis-7-(4-Benzyl-3,5-dimethylpiperazin-1-yl)-6-methoxyquinoline (D21)

The title compound was prepared from cis-1-benzyl-2,6-dimethylpiperazine(Org. Prep. Proc. 1976, 8, 19) and 7-bromo-6-methoxyquinoline (J. Org.Chem. 1990, 55, 2019) using a similar procedure to Description 2 (75%).

Description 22cis-7-(3,5-Dimethylpiperazin-1-yl)-6-methoxy-1,2,3,4-tetrahydroquinoline(D22)

A solution of D21 (6.8 g, 19 mmole) in EtOH (200 ml) and THF (200 ml)was hydrogenated over 10% Pd-C (1 g) at ambient temperature and pressurefor 48 h, then filtered through Kieselguhr and the filtrate hydrogenatedover Pt (1.5 g of PtO₂) at ambient temperature and 50 psi (344.8 Kpa)for 20 h. The mixture was filtered through Kieselguhr and the filtrateconcentrated under vacuum to afford the title compound as a colourlessoil (3.3 g, 63%).

Description 23cis-1-Acetyl-7-(3,5-dimethylpiperazin-1-yl)methoxy-1,2,3,4-tetrahydroquinoline(D23)

A stirred solution of D22 (2.4 g, 8.7 mmole) in DCM (100 ml) at 0° C.was treated with acetic anhydride (0.92 g, 9 mmole) and maintained at 0°C. for 6 h, then treated with excess 10% Na₂CO₃ solution, stirred for0.5 h, then extracted with DCM. The extract was dried and concentratedunder vacuum to afford the title compound as a yellow gum (2.7 g, 98%).

Description 24cis-1-Acetyl-6-methoxy-1,2,3,4-tetrahydro-7-(3,4,5-trimethylpiperazin-1-yl)quinoline(D24)

A stirred solution of D23 (2.7 g, 8.5 mmole) in MeOH (60 ml) at roomtemperature under Ar was treated with aqueous formaldehyde (3.2 ml of37% w/v, 40 mmole), followed by portionwise addition of NaBH₃CN (1.1 g,17 mmole). The pH of the mixture was adjusted to 6 by addition of formicacid and stirred at room temperature for 6 h, then concentrated undervacuum and the residue treated with 10% Na₂CO₃ solution and extractedwith DCM. The extract was dried, concentrated under vacuum and theresidue chromatographed on silica gel eluting with 0-20% MeOH/EtOAc toafford the title compound as a yellow solid (1.4 g, 50%).

Description 25cis-6-Methoxy-1,2,3,4-tetrahydro-7-(3,4,5-trimethylpiperazin-1-yl)quinoline(D25)

The title compound was prepared from D24 using a similar procedure toDescription 3 as a yellow solid (86%).

Description 26cis-1-Acetyl-6-(4-benzyl-3,5-dimethylpiperazin-1-yl)indoline (D26)

The title compound was prepared from cis-1-benzyl-2,6-dimethylpiperazine(Org. Prep. Proc. 1976, 8, 19) and 1-acetyl-6-bromoindoline(Heterocycles 1987, 26, 2817) using a similar procedure to Description 2as an off-white solid (53%).

Description 27 cis-1-Acetyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D27)

The title compound was prepared from D26 by hydrogenation over 10% Pd-Cusing a similar procedure to Example 45, followed by N-methylation usinga similar procedure to Description 24 to afford a white solid (59%).

Description 28 cis-6-(3,4,5-trimethylpiperazin-1-yl)indoline (D28)

The title compound was prepared from D27 using a similar procedure toDescription 3 to afford an off-white solid (96%).

Description 29cis-1-Acetyl-5-chloro-6-(3,4,5-trimethylpiperazin-1-yl)indoline (D29)

A solution of D27 (1.0 g, 3.5 mmole) in DCM (20 ml) under argon wastreated with N-chlorosuccinimide (929 mg, 7.0 mmole) and stirred at roomtemp. for 3 h. The mixture was washed with water, dried and evaporatedunder vacuum to a buff solid. Column chromatography on silica geleluting with 5% MeOH/DCM afforded the title compound as a white solid(670 mg, 60%).

Description 30 cis-5-Chloro-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D30)

The title compound was prepared from D29 using a similar procedure toDescription 3 to afford an off-white solid (72%).

Description 31cis-1-Acetyl-5bromo-6-(3,4,5-trimethylpiperazin-1-yl)indoline (D31)

A solution of D27 (884 mg, 3.1 mmole) in DCM (15 ml) at 0° C. underargon was treated with N-bromosuccinimide (819 mg, 4.6 mmole) andstirred at room temp. for 2 days. Additional NBS was added (150 mg, 0.84mmole) and stirring continued for 16 h. The mixture was washed with 10%Na₂CO₃ solution, dried and concentrated under vacuum. The residue waspurified by column chromatography on silica gel eluting with 5% MeOH/DCMto afford the title compound as a beige solid (440 mg, 39%).

Description 32 cis-5-Bromo-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D32)

A solution of D28 (250 mg, 1.0 mmole) in DCM (40 ml) under argon wastreated with trifluoroacetic anhydride (0.15 ml, 1.1 mmole) and stirredat room temp for 2 h. Evaporation in vacuo afforded a yellow oil (100%)which was re-dissolved in DCM (10 ml) and treated immediately withN-bromosuccinimide (356 mg, 2.0 mmole). The mixture was stirred underargon at room temp. for 16 h, washed with water, dried and evaporated invacuo to afford a yellow solid (100%), which was dissolved in MeOH (30ml) and treated under argon with Na₂CO₃ (500 mg, 4.7 mmole) then stirredat room temperature for 2 days. The mixture was evaporated in vacuo andpartitioned between water and DCM. The organics were dried andevaporated to afford the title compound as a beige solid (264 mg, 80%).

Description 33cis-1-Acetyl-5-ethyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline (D33)

A stirred suspension of D31 (200 mg, 0.55 mmole) in dry DMF (5 ml) wastreated with tributyl(vinyl)tin (0.24 ml, 0.83 mmole) and the mixturedegassed by bubbling argon through for 40 minutes. To the mixture wasadded Et₃N (0.15 ml, 1.1 mmole) andtetrakis(triphenylphosphine)palladium (0) (64 mg, 0.06 mmole) and themixture heated under argon at reflux for 18 h. On cooling, the mixturewas diluted with EtOAc (100 ml) and extracted with 0.5M HCl (2×). Theaqueous was basified (K₂CO₃), extracted with DCM, dried and evaporatedto a buff solid, which was dissolved in EtOH (10 ml) and hydrogenatedover 10% Pd/C (20 mg) at room temp. and atmospheric pressure for 2 days.Filtration through Celite (Diatomaceous Earth) and evaporation in vacuoafforded the title compound as a buff solid (100 mg, 62%).

Description 34 cis-5-Ethyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D34)

The title compound was prepared from D33 using a similar procedure toDescription 3 to afford a buff solid (84%).

Description 35 cis-6-(3,5-Dimethylpiperazin-1-yl)-5-methoxyindoline(D35)

The title compound was prepared from D4 by hydrogenation over 10% Pd/Cusing a similar procedure to Example 45 (98%), followed by hydrolysis in2M HCl using a similar procedure to Description 3 (80%) to afford theproduct as a pale brown solid

Description 36cis-1-Acetyl-5-methyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline (D36)

The title compound was prepared from D31 and tetramethyltin using asimilar procedure to Description 33 (20%).

Description 37 cis-5-Methyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D37)

The title compound was prepared from D36 using a similar procedure toDescription 3 (86%).

Description 38 cis-5-Fluoro-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D38)

The title compound was prepared from 1-acetyl-6-bromo-5-fluoroindoline(prepared by bromination of 5-fluoroindoline analogous to procedure inJ. Het. Chem. 1983, 20, 349, followed by N-acylation) by reaction withcis-3,5-dimethylpiperazine using similar procedure to Description 2(82%), followed by N-methylation using procedure similar to Description24 (69%), followed by hydrolysis as in Description 3 (96%). The productwas isolated as a pale yellow solid.

Description 39 N-(4-Acetyl-2-bromophenyl)-N-(2-methylallyl)acetamide(D39)

N-(4-Acetyl-2-bromophenyl)acetamide (25 g, 0.1 mole) in dry DMF (250 ml)was treated with sodium hydride (60%, 4.5 g, 0.11 mole) at 25° C. underargon with stirring for 1 h. 3-Bromo-2-methylpropene (1.1 ml, 0.11 mole)was added and the mixture stirred for a further 16 h. The mixture wasconcentrated in vacuo and partitioned between water and Et₂O. Theorganic phase was dried and concentrated in vacuo to give the titlecompound (32.8 g, 100%).

Description 40 1-(5-Acetyl-3,3-dimethylindolin-1-yl)ethanone (D40)

D39 (32.8 g, 0.1 mole) in toluene (3L) was stirred at 80° C. under argonand a solution of tri-n-butyltin hydride (40 ml) and AIBN (0.9 g) intoluene (250 ml) added over 25 minutes The mixture was heated at refluxfor 4 h and concentrated in vacuo. The whole was partitioned betweenEtOAc and aq.K₂CO₃ and the organic phase gave a residue which ontrituration with ether gave the title compound as a solid (10.7 g, 46%).

Description 41 5-Acetoxy-1-acetyl-3,3-dimethylindoline (D41)

D40 (10.7, 0.05 mole) in glacial AcOH (60 ml) was stirred at 25° C.under argon and a solution of peracetic acid (30%, 22 ml, 0.09 mole) inAcOH (10 ml) added over 30 minutes The mixture was kept at 25° C. for 20h, diluted with water (250 ml) and extracted with DCM. The organic phasewas washed (water, aq.metabisulfite, aq.K₂CO₃) dried (Na₂SO₄) andconcentrated to afford the title compound (10.2 g, 91%).

Description 42 1-(3,3-Dimethyl-5-hydroxyindolin-1-yl)ethanone (D42)

D41 (10.2, 0.04 mole) in MeOH (100 ml) and 2M NaOH (52 ml) was stirredat 25° C. under argon for 4 h. Acidification with conc. H₂SO₄ gave asolid which was collected by filtration, washed with water and dried invacuo to give D42 (7.8 g, 92%).

Description 43 1-(3,3-Dimethyl-5-methoxyindolin-1-yl)ethanone (D43)

D42 (7.8, 0.04 mole) in DMF (100 ml) was treated with methyl iodide(4.73 ml, 0.08 mole), K₂CO₃ (11.1 g, 0.08 mole) and stirred at 25° C.under argon for 24 h. The mixture was diluted with water (500 ml) andextracted exhaustively with Et₂O and concentrated to afford the titlecompound (6.4 g, 77%).

Description 44 1-(6-Bromo-3,3-dimethyl-5-methoxyindolin-1-yl)ethanone(D44)

D43 (6.4, 0.03 mole) in 2:1DCM:MeOH (420 ml) was stirred at 25° C. underargon; benzyltrimethylammonium tribromide (13.3 g, 0.34 mole) was addedportionwise and stirring continued for 5 h. The mixture was evaporatedto dryness and work-up with DCM/aq.K₂CO₃ afforded the title compound(8.7 g, 100%).

Description 45cis-1-Acetyl-3,3-dimethyl-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindoline(D45)

A mixture of palladium (II) acetate (650 mg),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.7 g) and cesium carbonate(13.5 g) in dry degassed 1,4-dioxane (200 ml) under argon was sonicatedat 28° C. for 0.5 h. This was treated with cis-2,6-dimethylpiperazine(4.6 g, 0.04 mole) and D44 (7.4 g, 0.025 mole) using a method similar tothat of Description 2 to give the title compound as a solid (1.6 g,19%).

Description 46cis-3,3-Dimethyl-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline(D46)

D45 was treated with aqueous formaldehyde and sodium cyanoborohydridefollowed by acid hydrolysis using a procedure similar to that ofDescriptions 24 and 3 to give the title compound as a waxy solid.MH⁺304.

Description 47 4-(2,5-Dimethylpyridin-4-yl)benzoic acid

The title compound was prepared from 4-bromo-2,5-dimethylpyridine (WO93/15062) and 4-carboxyphenylboronic acid using a similar procedure toDescription 18 as a white solid (67%).

Description 48cis-1,5-Diacetyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline

A solution of D31 (0.75 g, 2.0 mmole) and (1-ethoxyvinyl)tributyltin(1.08 g, 3.0 mmole) in dry DMF was treated withtetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmole) andtriethylamine (0.56 ml, 4.0 mmole). The mixture was heated to 100° C.under argon for 16 h. The cooled mixture was diluted with EtOAc (120ml), extracted with 2M HCl (3×30 ml) and the extracts were basified withK₂CO₃ and extracted with DCM (4×30 ml). The extracts were dried(Na₂SO₄), concentrated to dryness in vacuum and the residue waschromatographed on silica gel eluting with 5% MeOH/DCM to afford thecrude title compound as a brown oil (0.45 g, 67%).

Description 49 cis-5-Acetyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline

A solution of D48 (0.44 g, 1.34 mmole) in EtOH (5 ml) and 2M HCl (5 ml)was stirred at room temperature for 5 days. It was then concentratedunder vacuum, diluted with water (20 ml), basified with K₂CO₃ andextracted with DCM (3×15 ml). The extracts were dried (Na₂SO₄) andconcentrated under vacuum. The residue was chromatographed on silica geleluting with 0-10% MeOH/DCM to afford the title compound as a brown gum(0.21 g, 55%).

EXAMPLE 1cis-5-Methoxy-1-[4-(6-methylpyridin-2-yl)-1-naphthoyl]-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E1)

A suspension of D13 (92 mg, 0.35 mmole) in DCM (10 ml) was treated withoxalyl chloride (75 mg, 0.60 mmole) and stirred at room temperature for18 h, then concentrated under vacuum to leave the acid chloride as ayellow solid. This was re-dissolved in DCM (10 ml) and added to astirred solution of D3 (100 mg, 0.38 mmole) and pyridine (47 mg, 0.60mmole) in DCM (10 ml) at 0° C. under argon. The reaction mixture wasallowed to warm to room temperature and stir for 3 h, then treated withpolystyrene bound methylisocyanate (100 mg of 1.2 mmole/g) and stirredfor 18 h, then filtered through Kieselguhr. The filtrate was washed with10% Na₂CO₃ solution, dried (Na₂SO₄), concentrated under vacuum and theresidue purified by chromatography on basic alumina eluting with EtOActo afford the title compound as a yellow solid (110 mg, 60%).

¹H NMR (250 MHz, CDCl₃)—spectrum highly complex due to hindered rotationwith most peaks doubled up. Major peaks discernible: δ6.75 & 6.68 (2×s,together 1H=4H), 3.87 & 3.75 (2×s, together 3H=OMe), 3.16 & 3.00 (2×t,together 2H,=indoline CH ₂), 2.69 (s, 3H,=pyridyl Me), 2.34 & 2.12 (2×s,together 3H,=piperazine N-Me), 1.17 & 0.85 & 0.79 (3×d, together 6H,=3and 5-piperazine Me). MH⁺521.

Examples E2-E8 were prepared by a similar method to that of Example 1using D3 or D25 and an appropriate acid chloride derivative consistentwith the final product:

Example MH⁺ cis-5-Methoxy-1-[5-(6-methylpyridin-2-yl)-1-naphthoyl]- 5216-(3,4,5-trimethylpiperazin-1-yl)indoline (E2)cis-5-Methoxy-1-[5-(2-methyloxazol-5-yl)-1-naphthoyl]- 5116-(3,4,5-trimethylpiperazin-1-yl)indoline (E3)cis-1-(2,3-Dichlorobenzoyl)-5-methoxy-6-(3,4,5- 448/450trimethylpiperazin-1-yl)indoline (E4)cis-5-Methoxy-1-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3- 552yl)biphenyl-4-carbonyl]-6-(3,4,5-trimethylpiperazin-1- yl)indoline (E5)(acid ref: EP 0533268A1)cis-5-Methoxy-1-[(3-nitrophenyl)acetyl]-6-(3,4,5- 439trimethylpiperazin-1-yl)indoline (E6)cis-6-Methoxy-1-[4-(6-methylpyridin-2-yl)-1-naphthoyl]-1,2,3,4- 535tetrahydro-7-(3,4,5-trimethylpiperazin-1-yl)quinoline (E7)

EXAMPLE 8cis-1-[(2-Chloro-3-trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E8)

A solution of 2-chloro-3-trifluoromethylphenylacetic acid (954 mg, 4.0mmole) and D28 (950 mg, 3.87 mmole) in DCM (100 ml) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (766 mg,4.0 mmole) and 1-hydroxybenzotriazole hydrate (612 mg, 4.0 mmole) andstirred at room temp. for 0.5 h. The reaction mixture was washed with10% Na₂CO₃ solution, dried (Na₂SO₄) and concentrated under vacuum toafford the title compound as a pale yellow solid (1.15 g, 64%).

¹H NMR (250 MHz, CDCl₃) δ7.94 (d, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.38(t, 1H), 7.07 (d, 1H), 6.60 (dd, 1H), 4.19 (t, 2H), 3.98 (s, 2H), 3.45(br d, 2H), 3.17 (m, 2H), 2.53 (t, 2H), 2.34 (m, 2H), 2.22 (s, 3H), 1.13(d, 6H). MH⁺466/468.

EXAMPLE 9cis-1-[(2-Fluoro-3-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E9)

The title compound was prepared from2-fluoro-3-trifluoromethylphenylacetic acid (155 mg, 0.70 mmole) and D3(150 mg, 0.54 mmole) using a similar procedure to Example 8. The productwas obtained as a pale yellow oil (210 mg, 81%), which was converted toits hydrochloride salt as a beige solid.

¹H NMR (free base) (250 MHz, CDCl₃) δ7.91 (s, 1H), 7.65-7.50 (m, 2H),7.25 (t, 1H), 6.72 (s, 1H), 4.17 (t, 2H), 3.84 (s, 3H & s, 2H),3.35-3.25 (m, 2H), 3.19 (t,2H), 2.55-2.40 (m, 4H), 2.30 (s, 3H), 1.11(d, 6H). MH⁺480.

Examples E10-E43 were prepared by a similar method to that of Example 8using the appropriate indoline (D3, D28, D30, D32, D34, D35, D37 or D38)and the appropriate carboxylic acid consistent with the final product:

Example MH⁺cis-1-[(2,3-Dichlorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1- 448/450yl)-5-methoxyindoline (E10)cis-1-[(3-Chloro-2-fluorophenyl)acetyl]-6-(3,4,5- 416/418trimethylpiperazin-1-yl)indoline (E11)cis-1-[(2,3-Difluorophenyl)acetyl]-6-(3,4,5-trimethylpiperazin-1 400yl)indoline (E12)cis-1-[(2,3-Dichlorophenyl)acetyl]-6-(3,4,5-trimethylpiperazin- 432/4341-yl)indoline (E13) cis-1-[(2-Trifluoromethylphenyl)acetyl]-6-(3,4,5-432 trimethylpiperazin-1-yl)indoline (E14)cis-1-[(2,3-Dichlorophenyl)acetyl]-5-methoxy-6-(3,4,5- 462/464trimethylpiperazin-1-yl)indoline (E15)cis-1-[(2-Trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5- 462trimethylpiperazin-1-yl)indoline (E16)cis-1-[(3-Chloro-2-fluorophenyl)acetyl]-5-methoxy-6-(3,4,5- 446/448trimethylpiperazin-1-yl)indoline (E17)cis-1-[(2,3-Difluorophenyl)acetyl]-5-methoxy-6-(3,4,5- 430trimethylpiperazin-1-yl)indoline (E18)cis-5-Methoxy-1-[4-(6-methylpyridin-2-yl)-1-naphthylacetyl]-6- 535(3,4,5-trimethylpiperazin-1-yl)indoline (E19)cis-5-Chloro-1-[4-(6-methylpyridin-2-yl)-1-naphthoyl]-6-(3,4,5- 525/527trimethylpiperazin-1-yl)indoline (E20)cis-1-[4-(2,6-Dimethylpyridin-3-yl)-1-naphthoyl]-5-methoxy-6- 535(3,4,5-trimethylpiperazin-1-yl)indoline (E21) from D18cis-1-[4-(3,6-Dimethylpyrazin-2-yl)-1-naphthoyl]-5-methoxy-6- 536(3,4,5-trimethylpiperazin-1-yl)indoline (E22) from D19cis-5-Methoxy-1-[4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1- 536naphthoyl]-6-(3,4,5-trimethylpiperazin-1-yl)indoline (E23) (from D20)cis-1-[(2-Fluoro-3-trifluoromethylphenyl)acetyl]-5-methyl-6- 464(3,4,5-trimethylpiperazin-1-yl)indoline (E24)cis-1-[(2-Chloro-3-fluorophenyl)acetyl]-5-methoxy-6-(3,4,5- 446/448trimethylpiperazin-1-yl)indoline (E25)cis-1-[(2-Bromo-3-fluorophenyl)acetyl]-5-methoxy-6-(3,4,5- 490/492trimethylpiperazin-1-yl)indoline (E26)cis-1-[(2-Bromo-3-chlorophenyl)acetyl]-5-methoxy-6-(3,4,5- 508/509trimethylpiperazin-1-yl)indoline (E27)cis-1-[(2-Fluoro-3-trifluoromethylphenyl)acetyl]-6-(3,5- 466dimethylpiperazin-1-yl)-5-methoxyindoline (E28)cis-1-[(2-Chloro-3-trifluoromethylphenyl)acetyl]-6-(3,5- 482/484dimethylpiperazin-1-yl)-5-methoxyindoline (E29)cis-1-[(3-Chloro-2-fluorophenyl)acetyl]-6-(3,5- 432/434dimethylpiperazin-1-yl)-5-methoxyindoline (E30)cis-1-[(2-Chloro-3-trifluoromethylphenyl)acetyl]-5-methoxy-6- 496/498(3,4,5-trimethylpiperazin-1-yl)indoline (E31)cis-1-[(2-Fluoro-3-trifluoromethylphenyl)acetyl]-5-fluoro-6- 468(3,4,5-trimethylpiperazin-1-yl)indoline (E32)cis-1-[(3-Fluoro-2-trifluoromethylphenyl)acetyl]-5-methoxy-6- 480(3,4,5-trimethylpiperazin-1-yl)indoline (E33)cis-1-[(3-Chloro-2-cyanophenyl)acetyl]-5-methoxy-6-(3,4,5- 453/455trimethylpiperazin-1-yl)indoline (E34)cis-1-[(2-Acetyl-3-chlorophenyl)acetyl]-5-methoxy-6-(3,4,5- 470/472trimethylpiperazin-1-yl)indoline (E35)cis-1-[(3-Bromo-2-methylphenyl)acetyl]-5-methoxy-6-(3,4,5- 486/488trimethylpiperazin-1-yl)indoline (E36)cis-1-[(3-Cyano-2-methylphenyl)acetyl]-5-methoxy-6-(3,4,5- 433trimethylpiperazin-1-yl)indoline (E37)cis-5-Bromo-1-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6- 545/546(3,4,5-trimethylpiperazin-1-yl)indoline (E38)cis-5-Acetyl-1-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6- 508/510(3,4,5-trimethylpiperazin-1-yl)indoline (E39)cis-5-Methoxy-1-[(2-phenyl-3-(trifluoromethyl)pyrazol-4- 514ylcarbonyl]-6-(3,4,5-trimethylpiperazin-1-yl)indoline (E40)cis-6-(3,5-Dimethylpiperazin-1-yl)-1-[(4-(2,5-dimethylpyridin-4-yl)benzoyl]-5-methoxyindoline (E41) (from acid D47)cis-6-(3,5-Dimethylpiperazin-1-yl)-5-methoxy-1-[2′-methyl-4′- 539(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]indoline (E42) (acid ref:Description 47 in WO 97/34901)cis-6-(3,5-Dimethylpiperazin-1-yl)-5-methoxy-1-[2′-methyl-4′- 538(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]indoline (E43) (acidref: EP0533268A1)

EXAMPLE 44cis-6-(3,5-Dimethylpiperazin-1-yl)-5-methoxy-1-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]-indoline(E44)

Methyl [4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoate(Description 9 in WO 97/17351) was hydrolysed with 2M NaOH solution toafford the corresponding carboxylic acid, which was coupled with D35using a similar procedure to Example 8 to afford the title compound.Hydrochloride salt obtained as an off-white solid.

¹H NMR (250 MHz, CDCl₃) δ [rotamers—key signals quoted] 8.00 (br, 1H,indoline), 7.59 & 8.27 (Abq, 2H, J=8 Hz, pyridyl), 7.40 & 7.62 (Abq, 4H,J=8 Hz, phenyl), 6.75 (s, 1H, indoline), 3.85 (s, 3H, OMe), 3.10 (t, 2H,J=8 Hz), 2.68 (t, 2H, J=8 Hz), 2.47 (s, 3H, pyrMe), 2.14 (m, 2H), 1.13(br, 6H). MH⁺540.

EXAMPLE 45cis-6-(3,5-Dimethylpiperazin-1-yl)-5-methoxy-1-[4-(6-methylpyridin-2-yl)-1-naphthoyl]indoline(E45)

A solution of D6 (380 mg, 0.64 mmole) in EtOH (50 ml) and THF (50 ml)was treated with 10% Pd-C (300 mg) and stirred under a hydrogenatmosphere at ambient temperature and pressure for 70 h. The mixture wasfiltered through Kieselguhr and concentrated under vacuum. The residuewas purified by chromatography on basic alumina eluting with EtOAcfollowed by crystallisation from Et₂O to afford the title compound as ayellow solid (320 mg, 98%). MH⁺507.

EXAMPLE 46cis-1-[(2-Chloro-3-trifluoromethylphenyl)acetyl]-5-cyano-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E46)

A stirred mixture of E38 (67 mg, 0.12 mmole) and copper cyanide (43 mg,0.48 mmole) in DMF (2 ml) was heated to 130° C. for 16 h. The cooledmixture was added to conc. aqueous ammonia (50 ml), stirred for 30mins., then extracted with DCM (3×25 ml). The extracts were driedNa₂SO₄) and concentrated to dryness in vacuum. The residue was dissolvedin DCM (2 ml) and applied to an SCX resin cartridge (1 g) and the resineluted with DCM (×2), MeOH (×3) and the washings discarded. Finalelution with 1M NH₃ in MeOH (×2) afforded the title compound as a palebrown powder (26 mg, 43%). MH⁺491/493.

EXAMPLE 47cis-1-[(3-Aminocarbonyl-2-methylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E47)

To a stirred suspension of E37 (80 mg, 0.19 mmole) and K₂CO₃ (26 mg,0.19 mmole) in DMSO (1 ml) was added dropwise 30% aq. H₂O₂ soln.(0.1ml), then the mixture was warmed to 100° C. for 2 mins. and allowed tocool to room temperature. After 30 mins a further 0.1 ml of 30% aq. H₂O₂soln. was added and the mixture again warmed to 100° C. for 2 mins. andallowed to cool. This procedure was repeated twice more, and then themixture was stirred at room temperature for 16 h. It was diluted withwater (50 ml) and extracted with DCM (3×20 ml), the extracts dried(Na₂SO₄) and concentrated to dryness under vacuum. The residue wastriturated in Et₂O to afford the title compound as a cream powder (52mg, 63%). MH⁺451.

EXAMPLE 48cis-5-Methoxy-1-[4-(1-methylpiperidin-4-yl)-1-naphthoyl]-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E48)

A stirred solution of D3 (58 mg, 0.21 mmole) in toluene (5 ml) underargon was treated with 2M trimethylaluminium in toluene (0.13 ml, 0.25mmole), then stirred at room temperature for 0.75 h. A solution of D9(60 mg, 0.21 mmole) in toluene (5 ml) was added and the mixture washeated under reflux for 3.5 h, then allowed to cool to room temperature.The mixture was added to a 5 g silica gel column and eluted with 0-10%MeOH/DCM to afford a yellow oil. This was further purified bypreparative plate TLC on silica gel eluting with 9:1:0.1 DCM/MeOH/0.88NH₃ to afford the title compound as a white solid (39 mg, 35%). MH⁺ 527.

EXAMPLE 49cis-5-Methoxy-1-[4-(piperidin-4-yl)-1-naphthoyl]-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E49)

A solution of D12 (45 mg, 0.074 mmole) in DCM (10 ml) was treated withtrifluoroacetic acid (3 ml) and stirred at room temperature for 3 h,then concentrated under vacuum. The residue was dissolved in DCM andwashed with 10% Na₂CO₃ solution, dried and concentrated under vacuum.The residue was purified by silica gel chromatography followed bytrituration with Et₂O to afford the title compound as a pale brown solid(23 mg, 61%). MH⁺ 513.

EXAMPLE 50cis-1-[(2-Chloro-3-trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin-1-yl)indole(E50)

A solution of E8 (1.8 g, 3.86 mmole) in DCM (150 ml) was treated with asolution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (908 mg, 4.0mmole) in DCM (50 ml) and the mixture stirred at room temp. under argonfor 20 mins. The mixture was washed with 10% Na₂CO₃ solution, dried(Na₂SO₄), and evaporated to a brown oil. Column chromatography on silicagel (eluent 5% MeOH/DCM) afforded the title compound as a yellowsemi-solid (1.1 g, 61%), which was converted to its hydrochloride saltas a white solid.

¹H NMR (free base) (250 MHz, CDCl₃) δ8.06 (d, 1H), 7.72 (dd, 1H), 7.55(d, 1H), 7.42 (m, 3H), 6.98 (dd, 1H), 6.61 (d, 1H), 4.45 (s, 2H), 3.49(m, 2H), 2.59 (t, 2H), 2.40 (m, 2H), 2.31 (s, 3H), 1.15 (d, 6H). MH⁺464/466.

Examples E51-E56 were prepared by a similar method to that of Example50.

Example MH⁺ cis-1-[(2-Fluoro-3-trifluoromethylphenyl)acetyl]-5- 478methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indole (E51)cis-1-(2,3-Dichlorophenylaminocarbonyl)-5-methoxy- 4616-(3,4,5-trimethylpiperazin-1-yl)indole (E52) (from E60)cis-5-Methoxy-1-[4-(6-methylpyridin-2-yl)-1-naphthyl- 533acetyl]-6-(3,4,5-trimethylpiperazin-1-yl)indole (E53) (from E19)cis-1-[(3-Chloro-2-fluorophenyl)acetyl]-6-(3,5- 430/432dimethylpiperazin-1-yl)-5-methoxyindole (E54) (from E30)cis-1-[(2,3-Dichlorophenyl)acetyl]-6-(3,5-dimethyl- 446/448/449piperazin-1-yl)-5-methoxyindole (E55) (from E10)cis-1-[(2-Fluoro-3-trifluoromethylphenyl)acetyl]-5-fluoro-6- 466(3,4,5-trimethylpiperazin-1-yl)indole (E56) (from E32)

EXAMPLE 57cis-5-Methoxy-1-[4-(6-methylpyridin-2-yl)-1-naphthylaminocarbonyl]-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E57)

A stirred mixture of D13 (87 mg, 0.33 mmole), triethylamine (40 mg, 0.40mmole) and diphenylphosphoryl azide (96 mg, 0.35 mmole) in toluene washeated at reflux under argon for 0.5 h, then allowed to cool to roomtemperature and treated with a solution of D3 (70 mg, 0.25 mmole) in DCM(10 ml). The mixture was stirred at room temperature for 4 h, thentreated with polystyrene bound trisamine (80 mg of 3.6 mmole/g) andpolystyrene bound methylisocyanate (60 mg of 1.2 mmole/g) and stirred atroom temperature for 70 h, then filtered through Kieselguhr. Thefiltrate was washed with 10% Na₂CO₃ solution, dried (Na₂SO₄),concentrated under vacuum and purified by chromatography on basicalumina eluting with EtOAc, followed by trituration with Et₂O to affordthe title compound as a yellow solid (70 mg, 52%).

¹H NMR (250 MHz, CDCl₃) δ8.13 (d, 1H), 7.98 (d, 1H), 7.90 (d, 1H),7.78-7.70 (m, 2H), 7.61 (d, 1H), 7.60-7.45 (m, 2H), 7.34 (d, 1H), 7.21(d, 1H), 6.76 (s, 1H), 6.75 (s, 1H), 4.25 (t, 2H), 3.85 (s, 3H),3.38-3.21 (m, 4H), 2.67 (s, 3H), 2.55-2.40 (m, 4H), 2.30 (s, 3H), 1.09(d, 6H). MH⁺ 536.

Examples E58-E65 were prepared by a similar method to that of Example 57from indoline D3 or D37 and the appropriate carboxylic acid consistentwith the final product:

Example MH⁺ cis-5-Methoxy-1-[5-(6-methylpyridin-2-yl)-1- 536naphthylaminocarbonyl]-6-(3,4,5-trimethylpiperazin-1- yl)indoline (E58)cis-5-Methoxy-1-[5-(2-methyloxazol-5-yl)-1- 526naphthylaminocarbonyl]-6-(3,4,5-trimethylpiperazin-1- yl)indoline (E59)cis-1-(2,3-Dichlorophenylaminocarbonyl)-5-methoxy-6-(3,4,5- 463/465trimethylpiperazin-1-yl)indoline (E60)cis-1-(3-Chloro-2-fluorophenylaminocarbonyl)-5-methoxy-6- 447/449(3,4,5-trimethylpiperazin-1-yl)indoline (E61)cis-1-[3-Fluoro-2-(trifluoromethyl)phenylaminocarbonyl]-5- 481methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline (E62)cis-1-[2-Chloro-3-(trifluoromethyl)phenylaminocarbonyl]-5- 497/499methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline (E63)cis-1-[2-Chloro-3-methylphenyl)amiocarbonyl]-5-methoxy-6- 443/445(3,4,5-trimethylpiperazin-1-yl)indoline (E64)cis-1-[2-Chloro-3-(trifluoromethyl)phenyl)aminocarbonyl]-5- 481/483methyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline (E65)

EXAMPLE 66cis-1-(2,3-Dichlorophenylaminocarbonyl)-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E66)

A solution of D28 (10 mg, 0.04 mmole) in DCM (1 ml) was treated with2,3-dichlorophenyl isocyanate (10 mg, 0.05 mmole) and stirred at roomtemp for 16 h. The mixture was applied to an SCX resin cartridge (500mg) and the resin eluted with DCM (×2), MeOH (×3) and the washingsdiscarded. Final elution with 1M NH₃ in MeOH (×2) afforded the titlecompound as an off white solid (12 mg, 69%). MH⁺ 433/435.

Examples E67-E72 were prepared by a similar method to that of Example 66using indoline (D3, D30, D32 or D34) and the appropriate phenylisocyanate consistent with the final product.

Example MH⁺ cis-1-(2,3-Dichlorophenylaminocarbonyl)-5-chloro-6-(3,4,5-467/469 trimethylpiperazin-1-yl)indoline (E67)cis-1-(2,3-Dichlorophenylaminocarbonyl)-5-bromo-6-(3,4,5- 513/515trimethylpiperazin-1-yl)indoline (E68)cis-1-(2,3-Dichlorophenylaminocarbonyl)-5-ethyl-6-(3,4,5- 461/463trimethylpiperazin-1-yl)indoline (E69)cis-5-Methoxy-1-[2-(trifluoromethyl)phenylaminocarbonyl]-6- 433(3,4,5-trimethylpiperazin-1-yl)indoline (E70)cis-1-[2-Fluoro-3-(trifluoromethyl)phenylaminocarbonyl]-5- 480methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline (E71)cis-1-[2-Chloro-3-(trifluoromethyl)phenylaminocarbonyl]-3,3- 525dimethyl-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline (E72)

EXAMPLE 73cis-1-[(2-Chloro-3-trifluoromethyl)phenoxycarbonyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline(E73)

Triphosgene (40 mg, 0.13 mmole) was added to a stirred solution of D3(100 mg, 0.36 mmole) in DCM (10 ml) which was maintained at roomtemperature for 1 h, then treated with2-chloro-3-(trifluoromethyl)phenol (78 mg, 0.40 mmole) and triethylamine(0.062 ml, 0.44 mmole). The mixture was heated under reflux for 4 h,additional phenol (78 mg) and triethylamine (0.062 ml) added and heatingcontinued for a further 8 h. The mixture was washed with 10% K₂CO₃solution, dried and concentrated under vacuum. The title compound waspurified by chromatography on silica gel (84 mg, 47%). MH⁺ 498/500.

What is claimed is:
 1. A compound which iscis-6-(3,5-dimethylpiperazin-1-yl)-5-methoxy-1-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]indoline,its hydrochloride salt, or another pharmaceutically acceptable saltthereof.
 2. A pharmaceutical composition comprising a pharmaceuticallycarrier or excipient and the compound of claim 1 and/or apharmaceutically acceptable salt thereof.
 3. A method for treatingdepression which comprises administering to a mammal in need thereof aneffective amount of the compound of claim 1 and/or a pharmaceuticallyacceptable salt thereof, alone or in combination with a pharmaceuticallyacceptable carrier or excipient.